Our major objective is to study the active principle in the blood of animals and patients who have sustained an episode of severe shock which is capable of killing recipients of this blood. In recent years we have established that the material migrates electrophoretically with gamma globulin and behaves as aggregated (bound) gamma globulin upon ultracentrifugation, having an immunospecificity of gamma globulin. It is relatively heat stable and non-dialyzable; chromatographically pure preparations are colorless, soluble in water and alcohols, non-TCA precipitable, consisting of 16 different amino acids, mostly acidic, an isoelectric point of that of B-lactoglobulin and a molecular weight by gel filtration of about 49,000, at least 18% (9,000) of which is amino acids. It appears to be a glycopeptide. Physiologically it is able to kill recipient animals and demonstrates a remarkable toxicity to the heart, primarily by inhibition of ventricular contraction as demonstrated in the intact frog heart, the isolated perfused heart (Langendorf), the in vivo dog (open chest preparation) and the papillary muscle preparation (cat). It is our working hypothesis that during severe, prolonged shock, the stagnation and hypoxia secondary to selective compensatory ischemia cause an alteration in plasma protein(s) to form a "pretoxin" (CVTF precursor); subsequently, upon perfusion of lymphoid tissues (primarily the spleen) after transfusion of the patient or animal, white blood cell enzymes enter the circulation to cause the activation of the "pretoxin" to the CVTF (CardioVascular Toxic Factor). We demonstrated that the most active source of this white blood cell enzyme (other than our in vitro use of lysed white blood cells) is the effluent blood of the spleen of the hemorrhaged rat immediately following transfusion of its shed blood. In addition we reported that acid phosphatase can activate such pretoxin and that inhibitors of acid phosphatase can prevent CVTF formation in vivo and in vitro by inhibiting both the lysate and the phosphatase. We have recently shown that phosphorylated sugars, even when given after prolonged severe normally "irreversible" shock, prevents death. It is our intent to study this in patients.